These studies are designed to define and precisely characterize various molecular lesions occuring in the beta-globin gene cluster in patients with beta thalassemia or with syndromes associated with increased HbF production in adult life such as delta-beta thalassemia, or hereditary persistence of fetal hemoglobin (HPFH). Three new mutations have been characterized. A 12.0 kb deletion removes the delta and beta globin genes but spares the moderately repetitive Alu sequences. The phenotype of this mutation on interaction with a beta gene was found to be identical to the clinical phenotype produced interaction of the beta S with the Ghana type of HPFH-2 deletion. This deletion removes 70 kb of DNA including the Alu moderately repetitive DNA sequences. Thus, very different molecular defects may produce an identical clinical phenotype upon interaction with the beta S globin gene. Two additional mutations, one in a beta gene cluster and one in the alpha gene cluster are being characterized with respect to molecular genotype and clinical phenotype. A previously described mutation that involves two deletions as well as inversion of a 15 kb segment of the beta gene cluster has been functionally characterized. The intact G gamma gene exhibits features of gene activity, namely undermethylation and DNAseI hypersensitivity but a rearranged hybrid A gamma inverted delta gene appears transcriptionally inactive and is partially methylated. To investigate the mechanism by which premature termination dodons cause a quantitative deficiency of beta mRNA, precursor mRNA molecules are generated in vitro. The processing and nuclear to cytoplasmic transport of these RNA molecules are studied by microinjection into nuclei of Xenopus oocytes.